Cerebral Malformations in the HeCo Mouse and Human Cases

Background

In humans, cortical malformations are commonly associated with developmental delays, mental retardation and epilepsy. Available animal models are few and this represents a major limit in understanding precise mechanisms of abnormal cortical development and lowered epileptic threshold. A new autosomal recessive mouse model of cortical heterotopia (HeCo), that appeared spontaneously in the colony and shares some of the characteristics of the corresponding human disorder (developmental delay, increased tendency to epileptic seizures) was discovered in the applicant’s laboratory. The genetic origin has been elucidated and there is strong evidence that a little studied microtubule associated protein (MAP) mutation is responsible for the phenotype. The screening of human cases revealed that mutations of the otholog gene in humans produce severe brain malformations.

Hypotheses

The cortical malformation in mice and humans is due to abnormal migration and/or proliferation patterns.

Neural progenitors are abnormally located in the developing cerebral cortex.

Abnormal migration and proliferation patterns and abnormal neural progenitors location are due to a dysfunction of the microtubule cytoskeleton.

Methods

Different neural progenitors and proliferation markers will be used to determine the position of the different progenitor populations.Ex-vivo and in-utero electroporation of different plasmids in both mutant and control mice will be used to determine the migration pattern of post-mitotic neurons (speed, direction).

Expected results

These studies will identify a new heterotopia gene and pinpoint a novel biochemical pathway critical for cortical development. It will also highlight the little-studied theme of the involvement of ectopic proliferation in the pathophysiology of subcortical heterotopia.

The mouse mutant HeCo allowed to discover a new gene involved in cortical development that is also responsible for human cerebral malformations. It is a rare model to study cortical development but also epilepsy. It represents a good example of translational medicine and therefore could permit to better understand human cases and refine anti-epileptic treatments. Finally, as it has been often demonstrated in the past, the discovery of a new gene could also be a tool for researches outside the scope of the present project.